No Altitude Required: Differential ventilatory and blood acid-base homeostasis between unacclimatized lowlanders and Tibetan highlanders at 1,400 m

Tibetan highlanders (TH) possess physiological adaptations supporting ventilation, oxygenation, and acid-base regulation with acclimatization to chronic hypobaric hypoxia. While well-characterized at high-altitude, it is unclear whether these traits are evident at low-altitude, independent of environmental hypoxic stimuli. To evaluate baseline physiological differences, we compared variables related to ventilatory, blood oxygen, and acid-base balance between unacclimatized ancestral lowlanders (LL; n=29) and TH (n=31) residing at 1,400 m, a subthreshold altitude not expected to elicit ventilatory or renal acclimatization. Heated hand capillary blood samples were analyzed for hemoglobin (Hb c ), oxygen content (C c O 2 ), alveolar ventilation (V̇ A ), steady-state chemoreflex drive (SSCD), partial pressure of carbon dioxide (P c CO 2 ), bicarbonate (HCO 3 - c ), and pH c . TH demonstrated significantly higher V̇ A (4.6±0.4 vs. 4.8±0.3 l/min; +5.2%; P=0.0101) and SSCD (11.9±1.9 vs. 13.2±1.9 a.u.; +10.3%; P=0.0127) than LL, despite equivalent SpO 2 (P=0.8882). Additionally, TH exhibited lower P c CO 2 (37.9±2.8 vs. 36.0±2.5 mmHg; −5%; P=0.0086) and HCO 3 - c (22.9±1.4 vs. 21.5±1.6 mmol/l; −6.1%; P=0.0007) compared to LL, with no difference in pH c (P=0.256).The reduction of HCO 3 - c in TH was greater than expected from passive chemical buffering alone, suggesting differential renal handling breathing ambient air at low altitude. These findings suggest that TH maintain a distinct ventilatory and acid-base homeostatic set-point at low altitude, characterized by enhanced resting ventilatory drive and renal excretion of HCO 3 - . These traits, characterized at low altitude, suggest that developmental exposure to hypoxia and/or Tibetan ancestry is associated with developed or evolved physiological traits that optimize respiratory and acid-base homeostasis during high-altitude ascent.